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Anterior dissection of the rectum in the male pelvis represents one of the most complex phases of total meso-rectal excision. However, the possible existence of different anatomical planes is controversial and the exact anatomical topography of Denonvilliers' fascia is still debated. The aim of the study is to accurately define in a cadaveric simulation model the existence and boundaries of Denonvilliers' fascia, identifying the anatomical planes suitable for surgical dissection. The pelvises of 31 formalin-preserved male cadavers were dissected. Careful and detailed dissection was carried out to visualize the anatomical structures and the potential dissection planes, simulating an anterior meso-rectum dissection. Denonvilliers' fascia was identified in 100% of the pelvises, as a single-layer fascia that originates from the peritoneal reflection and descends until its firm adhesion to the prostate capsule. The fascia divides the space providing an anterior and a posterior plane. Anteriorly to the fascia, during the caudal dissection, its firm adhesion to the prostate capsule forces to section it sharply. The cadaveric simulation model allowed an accurate description of Denonvilliers' fascia, defining several planes for anterior dissection of the meso-rectum., (© 2022. The Author(s).)

Background and Objective: Children born small for gestational age (SGA) show higher risk of neurodevelopmental and cognitive abnormalities. The objective of this study is to determine in children born SGA the neurodevelopment during the first 2 years of life and to establish the influence of anthropometric data, gestational age, multiple gestation and perinatal factors., Patients and Method: Observational, prospective, descriptive and analytical study of the neurocognitive assessment performed, with Brunet-Lézine test, on SGA children (n = 91) from 3 to 24 months of age, comparing with own controls., Results: Ninety-one SGA children, 47% girls, 83.5% single pregnancies; mean gestational age 37.7 weeks (standard deviation (SD) 2.1). Weight at birth 2053 g (SD 433.1), length 43.9 cm (SD 2.6) and head circumference 31.7 cm (SD 1.7). The SGA population shows significantly lower neurodevelopment than the control population, with a tendency to improve during the first 2 years of life. There are no differences by sex. SGA children born to multiple gestations have lower neurodevelopment only during the first year of life. There is a direct and positive correlation between weight, length and head circumference with neurocognitive development at 6, 9, 12 and 18 months. Gestational age correlated with better neurodevelopment at 3 and 6 months., Conclusions: Children born SGA present lower neurodevelopment than the control population. A greater impact on weight, length, and head circumference at birth is correlated with poorer neurocognitive development. Multiparity does not show significant influence on neurodevelopment evolution., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Background/aim: In the Santander Bay (Cantabria, northern Spain), a ferromanganese alloy plant is located. Our objective was to characterize the Mn personal exposure of adult healthy volunteers living in this highly Mn exposed region, and to determine its association with a poorer cognitive function., Methods: Cross-sectional study analyzing 130 consecutive participants. Cognitive function was assessed by Stroop Color Word, Verbal Fluency tests, Trail Making Test (TMT), Digit Span (WAIS III) and Rey Osterrieth Complex Figure (ROCF) tests and crude scores were standardized according to NEURONORMA norms. Exposure to Mn was assessed in terms of source distance, by Personal Environmental Monitors (PEMs) allowing the separation of fine (PM2.5) and coarse (PM10-2.5) particles (obtaining the bioaccessible fraction by in-vitro bioaccessibility tests), and by biomarkers (blood, hair and fingernails). Age, sex, study level and number of years of residence were predefined as confounding variables and adjusted Mean Differences (MDs) were obtained., Results: Statistically significant lower scores (negative MDs) in all test were observed when living near the industrial emission source, after adjusting for the predefined variables. Regarding PEMs results, statistically significant lower scores in all Stroop parts were obtained in participants with higher levels of Total Mn in All fractions (PM10). For Verbal Fluency tests, negative MDs were obtained for both bioaccessible fractions. Digit Span Backward scores were lower for those with higher levels in the bioaccessible coarse fraction, and negative MDs were also observed for the ROCF Delayed part and the non-bioaccessible fine fraction. As regards to Mn in fingernails, adjusted MDs of -1.60; 95%CI (-2.57 to -0.64) and -1.45; 95%CI (-2.29 to -0.61) for Digit Span Forward and Backward parts were observed., Conclusions: Our results support an association between poorer cognitive function and environmental airborne Mn exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The effectiveness of venetoclax (VEN) in relapsed or refractory acute myeloid leukemia (RR-AML) has not been well established. This retrospective, multicenter, observational database studied the effectiveness of VEN in a cohort of 51 RR-AML patients and evaluated for predictors of response and overall survival (OS). The median age was 68 years, most were at high risk, 61% received ≥2 therapies for AML, 49% had received hypomethylating agents, and ECOG was ≥2 in 52%. Complete remission (CR) rate, including CR with incomplete hematological recovery (CRi), was 12.4%. Additionally, 10.4% experienced partial response (PR). The CR/CRi was higher in combination with azacitidine (AZA; 17.9%) than with decitabine (DEC; 6.7%) and low-dose cytarabine (LDAC; 0%). Mutated NPM1 was associated with increased CR/CRi. Median OS was 104 days (95% CI: 56-151). For the combination with AZA, DEC, and LDAC, median OS was 120 days, 104 days, and 69 days, respectively; p = 0.875. Treatment response and ECOG 0 influenced OS in a multivariate model. A total of 28% of patients required interruption of VEN because of toxicity. Our real-life series describes a marginal probability of CR/CRi and poor OS after VEN-based salvage. Patients included had very poor-risk features and were heavily pretreated. The small percentage of responders did not reach the median OS.

About 40% of traumatic injuries in sports are related to the knee. Of these, 33% require arthroscopic surgery. The rehabilitative ultrasound imaging technique is a simple method to obtain objective real-time results on the state and measurement of the musculoskeletal tissue and its use can represent an important change in the process of functional diagnosis and recovery of these injuries. The aim was to quantify the differences in the thickness, muscle contraction time, and muscle relaxation time of the rectus femoris muscle between individuals with knee arthroscopy and healthy individuals and to verify the reliability of the inter-examiner measurements in these ultrasound variables. An observational case-control study with individuals (18−60 years aged) who underwent surgery for anterior cruciate ligament through knee arthroscopy a year or more before. A total of 38 subjects were divided into 2 groups, case and control. Ultrasound measurements were taken of the following outcomes: thickness at rest and contraction, muscle contraction time, and muscle relaxation time of the rectus femoris muscle. Excellent inter-examiner reliability was obtained for all ultrasound measurements (ICC3.3 > 0.90). No significant changes were found in the rate of contraction or rest of the rectus femoris muscle. On the other hand, if significant changes in the thickness of the rectus femoris muscle were found between control and case group. Arthroscopic surgery for anterior cruciate ligament reconstruction does not appear to modify function but does modify the thickness of the rectus femoris muscle on ultrasound examination. Ultrasound appears to be a reliable tool for the study of these measurements in the rectus femoris muscle.

Urinary incontinence is considered a health problem that both elderly and young people can suffer, most often elderly women. This problem can lead to difficulties in establishing social relationships and dependence, negatively affecting the quality of life of the people who suffer from it. To evaluate and analyze the studies that demonstrate the efficacy of interventions based on the neuromodulation of the posterior tibial nerve as a treatment for the control of urinary incontinence. The search period for articles focused on those published between March 2011 to March 2021, in five databases (Pubmed, Cochrane Library, Scielo, Google Academic and WOS) based on the clinical question, using the keywords derived from the DeCS and MeSH thesauri, combined with the Boolean operators "AND", "NOT" and "OR". The search was limited to publications from the last 10 years, in English and Spanish. After applying the selection criteria and evaluating the quality of the methodology, 5.28% ( n = 27) of the 511 results were included with filters: 9 systematic reviews, 10 cohorts and 8 randomized controlled trials. After comparing the different articles, it was found that percutaneous stimulation of the tibial nerve is a suitable technique for treating overactive bladder. It is a promising technique in case of pelvic floor dysfunctions and effective for the control of urinary incontinence.

Background: Coronavirus disease 2019 (COVID-19) infection is a major public health problem in the world and reinfections are becoming more frequent. Our main objective was to describe the epidemiological, clinical, and genomic characteristics of the confirmed cases of reinfection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the capital of Lima and Callao, Peru., Methods: We searched in the Peruvian laboratory information system from April 2020 up to May 2021, looking for cases having 2 positive molecular tests for SARS-CoV-2 with more than 90 days between them. We performed genomic sequencing to the available pairs of samples and described the clinical characteristics, epidemiological impact, and genomic analysis of the confirmed reinfections., Results: There were 1 694 164 people with a positive diagnostic test for SARS-CoV-2 in Lima/Callao during the study period. Of these, 1695 had 2 positive molecular tests with more than 90 days between them. Two hundred eleven had both samples available for genomic analysis according to our selection criteria, and these were retrieved and submitted to sequencing. Thirty cases were confirmed to be SARS-CoV-2 reinfections with 2 different lineages in the 2 episodes. The variant Lambda (C.37) was the most common during the second infection and accounted for 19 (63.3%) of the 30 cases., Conclusions: We report 30 cases of confirmed SARS-CoV-2 reinfections. The Lambda variant was the most common cause of the second infections, in concordance with its predominant circulation during Peru's second wave. This report describes the largest series of confirmed reinfections by SARS-CoV-2 in Latin America.We describe the epidemiological, clinical, and genomic characteristics of the confirmed cases of reinfection by severe acute respiratory syndrome coronavirus 2 in Lima and Callao, durante la segunda ola en Peru. The Lambda variant (C.37) was the most common cause of the second infections., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The emergence of Klebsiella pneumoniae isolates carrying novel bla KPC variants conferring ceftazidime-avibactam (CAZ/AVI) resistance is being increasingly reported. We evaluated the accuracy of phenotypic methods commonly used in routine clinical laboratories in the detection of novel K. pneumoniae carbapenemase (KPC) enzymes. Additionally, we characterized by whole-genome sequencing (WGS) the KPC-ST307-K. pneumoniae isolates recovered in our hospital before and after CAZ/AVI therapy. Rectal colonization or infection by carbapenem-resistant KPC-3 K. pneumoniae isolates (imipenem MIC, 16 mg/L; meropenem MIC, 8 to >16 mg/L) and CAZ/AVI-susceptible isolates (CAZ/AVI MIC, 1 to 2 mg/L) were first detected in three intensive care unit (ICU) patients admitted between March 2020 and July 2020. KPC K. pneumoniae isolates with increased CAZ/AVI MICs (8 to 32 mg/L) and carbapenem susceptibility (imipenem and meropenem MIC, <1 mg/L) were recovered within 6 to 24 days after CAZ/AVI treatment. WGS confirmed that all KPC K. pneumoniae isolates belonged to the sequence type 307 (ST307) high-risk clone and carried identical antimicrobial resistance genes and virulence factors. The presence of the novel bla KPC-46 , bla KPC-66 , and bla KPC-92 genes was confirmed in the K. pneumoniae isolates with increased CAZ/AVI MICs and restored carbapenem activity. KPC production was confirmed by immunochromatography, the eazyplex Superbug CRE system, and the Xpert Carba-R assay in all KPC K. pneumoniae isolates, but not in any isolate using chromogenic agar plates for carbapenemase producers (ChromID-CARBA), the KPC/MBL/OXA-48 Confirm kit, and the β-CARBA test. Nevertheless, all grew in chromogenic agar plates for extended-spectrum β-lactamase (ESBL) producers (ChromID-ESBL). We report the failure of the most common phenotypic methods used for the detection of novel KPC carbapenemases but not of rapid molecular or immunochromatography assays, thus highlighting their relevance in microbiology laboratories.

Novel β-lactam-β-lactamase inhibitor combinations currently approved for clinical use are poorly active against metallo-β-lactamase (MBL)-producing strains. We evaluated the in vitro activity of cefepime-taniborbactam (FTB [formerly cefepime-VNRX-5133]) and comparator agents against carbapenemase-producing Enterobacterales ( n  = 247) and carbapenem-resistant Pseudomonas species ( n  = 170) clinical isolates prospectively collected from different clinical origins in patients admitted to 8 Spanish hospitals. FTB was the most active agent in both Enterobacterales (97.6% MIC FTB , ≤8/4 mg/L) and Pseudomonas (67.1% MIC FTB , ≤8/4 mg/L) populations. The MIC FTB was >8 mg/L in 6/247 (2.4%) Enterobacterales isolates (3 KPC-producing Klebsiella pneumoniae isolates, 1 VIM-producing Enterobacter cloacae isolate, 1 IMP-producing E. cloacae isolate, and 1 NDM-producing Escherichia coli isolate) and in 56/170 (32.9%) Pseudomonas isolates, 19 of them carbapenemase producers (15 producers of VIM, 2 of GES, 1 of GES+VIM, and 1 of GES+KPC). Against the Enterobacterales isolates with meropenem MICs of >2 mg/L (138/247), FTB was the most active agent against both serine-β-lactamases (107/138) and MBL producers (31/138) (97.2 and 93.5% MIC FTB , ≤8/4 mg/L, respectively), whereas the activity of comparators was reduced, particularly against the MBL producers (ceftazidime-avibactam, 94.4 and 12.9%, meropenem-vaborbactam, 85.0 and 64.5%, imipenem-relebactam, 76.6 and 9.7%, ceftolozane-tazobactam, 1.9 and 0%, and piperacillin-tazobactam, 0 and 0%, respectively). Among the meropenem-resistant Pseudomonas isolates (163/170; MIC, >2 mg/L), the activities of FTB against serine-β-lactamase (35/163) and MBL (43/163) producers were 88.6 and 65.1%, respectively, whereas the susceptibilities of comparators were as follows: ceftazidime-avibactam, 88.5 and 16.0%, meropenem-vaborbactam, 8.5 and 7.0%, imipenem-relebactam, 2.9 and 2.3%, ceftolozane-tazobactam, 0 and 2.3%, and piperacillin-tazobactam, 0 and 0%, respectively. Microbiological results suggest FTB as a potential therapeutic option in patients infected with carbapenemase-producing Enterobacterales and carbapenem-resistant Pseudomonas isolates, including MBL producers.

This review has identified evidence about pseudomyopia as the result of an increase in ocular refractive power due to an overstimulation of the eye's accommodative mechanism. It cannot be confused with the term "secondary myopia", which includes transient myopic shifts caused by lenticular refractive index changes and myopia associated with systemic syndromes. The aim was to synthesize the literature on qualitative evidence about pseudomyopia in terms that clarify its pathophysiology, clinical presentation, assessment and diagnosis and treatment. A comprehensive literature search of PubMed and the Scopus database was carried out for articles published up to November 2021, without a data limit. This review was reported following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Following inclusion and exclusion criteria, a total of 54 studies were included in the qualitative synthesis. The terms pseudomyopia and accommodation spasm have been found in most of the studies reviewed. The review has warned that although there is agreement on the assessment and diagnosis of the condition, there is no consensus on its management, and the literature describes a range of treatment.

Mechanical forces regulate multiple essential pathways in the cell. The nuclear translocation of mechanoresponsive transcriptional regulators is an essential step for mechanotransduction. However, how mechanical forces regulate the nuclear import process is not understood. Here, we identify a highly mechanoresponsive nuclear transport receptor (NTR), Importin-7 (Imp7), that drives the nuclear import of YAP, a key regulator of mechanotransduction pathways. Unexpectedly, YAP governs the mechanoresponse of Imp7 by forming a YAP/Imp7 complex that responds to mechanical cues through the Hippo kinases MST1/2. Furthermore, YAP behaves as a dominant cargo of Imp7, restricting the Imp7 binding and the nuclear translocation of other Imp7 cargoes such as Smad3 and Erk2. Thus, the nuclear import process is an additional regulatory layer indirectly regulated by mechanical cues, which activate a preferential Imp7 cargo, YAP, which competes out other cargoes, resulting in signaling crosstalk., (© 2022. The Author(s).)

Objective: Post-COVID syndrome can impact against every sphere of daily live. The objective of this work was to detect the factors correlated with a better or worse physical recovery four months after hospital discharge from a hospitalization in ICU due to COVID-19., Methods: Prospective descriptive study of 125 patients valued by the Rehabilitation Service during hospitalization in ICU, from March 12 th to December 31 st , 2020. Data from 76 patients was analysed with clinical follow up after 1, 2 and 4 months of hospital discharge. Variables on personal, hospitalary, functional symptoms/signals and physical recovery were analysed with mean ± standard deviation, counting (percentage), T-student test and Fisher test., Results: After one month, fatigue was observed in 60 (80%) patients and dyspnoea in 47 (62%). After two months, fatigue in 37 (55%), dyspnoea in 25 (33%), shoulder pain in 33 (43%), average QuickDASH was 22.7 (11.3-50), Sit-to-Stand Test in 30 seconds 11.5 (10-13) and 6-minute walk test 390 meters (326-445). In the fourth month, 25 (53%) had returned to work and had an average of the physical recovery of 79.1%±18.3%. There was no correlation between physical recovery ≥75% and the first month data, but there certainly was a correlation between some second month variables, such as fatigue (p=0.001), dyspnoea (p=0.035), QuickDASH (p=0.001) and 6-minute walk test (p=0.021)., Conclusions: Symptoms (fatigue and dyspnoea) and functional scales (QuickDASH and 6-minute walk test) after 2 months predict a better/worsen physical recovery after 4 months of hospital discharge., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

In the recent years, research in oncologyhas focused on liquid biopsies, which rely on thedetection of cancer-derived components, includingcirculating tumor cells (CTCs), circulating tumor DNA(ctDNA), circulating free RNA (cfRNA), and extracellularvesicles (EVs), in the biofluids of patients, providinggenomic, epigenetic and transcriptomic, informationabout tumors and metastatic sites. In this reviewwe collect current evidence regarding the potentialof liquid biopsies for the diagnosis and follow-up ofuro-oncology patients, as well as the advantages andlimitations of these approaches. Although promising,the way in which this methodology must be incorporatedinto the clinical routine needs to be still definedboth at the pre-analytical and analytical level beforetheir clinical utility is demonstrated.

Most publications on pediatric COVID-19 in Spain were performed at the beginning of the pandemic when some diagnostic tools were not widely available. This study aims to show the real spectrum of the infection based on wide detection of cases due to symptoms and contact tracing. A descriptive and analytical observational study was performed including pediatric cases (0 to 14 years) from the region of Aragón between May 12 and October 31, 2020. Diagnostics was by PCR detection of viral RNA, rapid antigen detection test, or positive IgG serology. There were 5933 positive children included. Of them, 49.03% were women. The mean age was 7.53 ± 4.28 years. The source of infection could not be determined in 17.8% of cases. As for the rest, was determined to be within the family environment in 67.8%. The percentage of asymptomatic patients was 50.3%. Among symptomatic patients, fever (58.1%) and cough (46.7%) were the most frequent symptoms. Hospitalization was required in 0.52% of infected, intensive care unit admission was on 0.05%, and there was one death (0.02%). Children under the age of one presented some symptoms more frequently (71.6% vs 48.5%; OR 2.68; 95% CI 2.08 to 3.45; p < 0.001) and required more hospitalizations (3.9% vs 0.34%; OR 11.52; 95% CI 5.65 to 23.52; p < 0.001).Conclusion: In our environment, SARS-CoV-2 infection is like other mild respiratory viral infections in the population under the age of 15. The contagion occurs mainly in the family environment, the number of asymptomatic is high, being the symptoms mild and the complications very infrequent. What is Known: • Pediatric infection produced by SARS-CoV-2 has manifested as a mild disease in relation to adult age, although with higher affectation at the youngest ages. • Nearly all studies on epidemiology and clinical spectrum of the disease were conducted with patients diagnosed at the beginning of the pandemic. By then, diagnostic tools were only available in hospitals and in emergency units. What is New: • Once diagnostic means were available in primary care medicine and were used not only for the diagnosis of clinical symptoms of the patient, but for the tracing of case contacts, a much more precise approach to the epidemiology and clinical manifestations of the disease was allowed, as described in this study., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The main aim was to evaluate changes in urea cycle enzymes in NAFLD patients and in two preclinical animal models mimicking this entity. Seventeen liver specimens from NAFLD patients were included for immunohistochemistry and gene expression analyses. Three-hundred-and-eighty-two biopsy-proven NAFLD patients were genotyped for rs1047891, a functional variant located in carbamoyl phosphate synthetase-1 (CPS1) gene. Two preclinical models were employed to analyse CPS1 by immunohistochemistry, a choline deficient high-fat diet model (CDA-HFD) and a high fat diet LDLr knockout model (LDLr -/-). A significant downregulation in mRNA was observed in CPS1 and ornithine transcarbamylase (OTC1) in simple steatosis and NASH-fibrosis patients versus controls. Further, age, obesity (BMI > 30 kg/m 2 ), diabetes mellitus and ALT were found to be risk factors whereas A-allele from CPS1 was a protective factor from liver fibrosis. CPS1 hepatic expression was diminished in parallel with the increase of fibrosis, and its levels reverted up to normality after changing diet in CDA-HFD mice. In conclusion, liver fibrosis and steatosis were associated with a reduction in both gene and protein expression patterns of mitochondrial urea cycle enzymes. A-allele from a variant on CPS1 may protect from fibrosis development. CPS1 expression is restored in a preclinical model when the main trigger of the liver damage disappears., (© 2022. The Author(s).)

Introduction: Short stature is the most frequent reason for consultation in Pediatric Endocrinology consultations and sometimes requires treatment with growth hormone. The aim of the study was to analyze the response to treatment based on its onset in pubertal or prepubertal stages and to analyze the possible benefit of an early onset., Patients and Methods: Longitudinal, retrospective and observational study in 139 patients treated for idiopathic growth hormone deficiency up to adult height., Main Variables Studied: (a) genetic background: maternal, paternal and genetic height; (b) perinatal history; (c) anthropometry during follow-up and at pubertal onset: weight, height, body mass index; (d) variables during follow-up and at pubertal onset: growth rate, bone age and growth prognosis. Final response variables: adult height, adult height with respect to target height, adult height with respect to initial growth prediction, adult height with respect to initial height at the start of treatment and adult height with respect to height at pubertal onset., Results: Total pubertal gain was 0.84 ± 0.6 SD. 61.9% of the patients started treatment with rhGH in prepuberty. The initiation of treatment in the prepubertal stage and a higher total pubertal gain are correlated with a better final height (P = 0.001 and r = 0.507, P = 0.00, respectively). Furthermore, a longer duration of treatment in pre-puberty is correlated with a better final response (r = 0.328, P = 0.00)., Conclusions: The start of treatment in the prepubertal stage and its longer duration during this period are determining factors to achieve a good long-term response. Total pubertal gain was greater in patients who started treatment in the pubertal stage., (Copyright © 2022 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple α-ketoglutarate-dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate-mediated mechanisms: suppression of CD8+ T-cell activity and tumor cell-autonomous inactivation of TET2 DNA demethylase. Pharmacologic mIDH1 inhibition stimulates CD8+ T-cell recruitment and interferon γ (IFNγ) expression and promotes TET2-dependent induction of IFNγ response genes in tumor cells. CD8+ T-cell depletion or tumor cell-specific ablation of TET2 or IFNγ receptor 1 causes treatment resistance. Whereas immune-checkpoint activation limits mIDH1 inhibitor efficacy, CTLA4 blockade overcomes immunosuppression, providing therapeutic synergy. The findings in this mouse model of cholangiocarcinoma demonstrate that immune function and the IFNγ-TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for potentiating efficacy., Significance: Mutant IDH1 inhibition stimulates cytotoxic T-cell function and derepression of the DNA demethylating enzyme TET2, which is required for tumor cells to respond to IFNγ. The discovery of mechanisms of treatment efficacy and the identification of synergy by combined CTLA4 blockade provide the foundation for new therapeutic strategies. See related commentary by Zhu and Kwong, p. 604. This article is highlighted in the In This Issue feature, p. 587., (©2021 American Association for Cancer Research.)

Imaging techniques based on mass spectrometry or spectroscopy methods inform in situ about the chemical composition of biological tissues or organisms, but they are sometimes limited by their specificity, sensitivity, or spatial resolution. Multimodal imaging addresses these limitations by combining several imaging modalities; however, measuring the same sample with the same preparation using multiple imaging techniques is still uncommon due to the incompatibility between substrates, sample preparation protocols, and data formats. We present a multimodal imaging approach that employs a gold-coated nanostructured silicon substrate to couple surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS) and surface-enhanced Raman spectroscopy (SERS). Our approach integrates both imaging modalities by using the same substrate, sample preparation, and data analysis software on the same sample, allowing the coregistration of both images. We transferred molecules from clean fingertips and fingertips covered with plasticine modeling clay onto our nanostructure and analyzed their chemical composition and distribution by SALDI-MS and SERS. Multimodal analysis located the traces of plasticine on fingermarks and provided chemical information on the composition of the clay. Our multimodal approach effectively combines the advantages of mass spectrometry and vibrational spectroscopy with the signal enhancing abilities of our nanostructured substrate.

Purpose: To analyze astigmatism axis changes after tropicamide and phenylephrine combined instillation., Method: One hundred and thirty-one eyes from 66 patients enrolled this cross-sectional study. An extensive ocular examination was carried out prior to tropicamide and phenylephrine instillation. Power and axis value from flat, steep, and mean keratometry were calculated using an Auto Kerato-Refractometer (AKR). Later, topography and tomography maps were evaluated with Pentacam HR® (Oculus, Wetzlar, Germany). Subsequently, a single drop of tropicamide 1% and phenylephrine hydrochloride 10% were instilled twice, with a five-minute gap between each instillation. After 30 minutes, the AKR and Pentacam HR® tests were repeated., Results: Incyclotorsion was found in 59 eyes (45.1%) and mean absolute incyclotorsion change was 3.91 ± 3.62 degrees (0.10 to 14.20). Excyclotorsion was found in 72 eyes (54.9%) and mean excyclotorsion change was 4.99 ± 5.94 degrees (0.20 to 36.20). We observed that 74.6% and 68.1% of eyes experienced incyclotorsion and excyclotorsion within 0 to 5 degrees, respectively. Fewer patients experienced incyclotorsion and excyclotorsion changes within 5 to 10 degrees, precisely 11.8% and 19.4%, respectively. Eyes that experienced over 10 degrees of incyclotorsion and excyclotorsion were 13.6% and 12.5%, respectively., Conclusion: Astigmatism axis could change after combined tropicamide and phenylephrine instillation. Reference axis marking in astigmatism correction surgery should be performed under the same circumstances as the astigmatism axis has been measured.

Purpose: Anaemia is a global health concern, with iron deficiency anaemia (IDA) causing approximately 50% of cases. Affecting mostly the elderly, pregnant and adult women and children, physiopathology of IDA in relation to the gut microbiome is poorly understood. Therefore, the objective of this study is to analyse, in an animal model, the effect of IDA on the gut microbiome along the gastrointestinal tract, as well as to relate intestinal dysbiosis to changes in microbial metabolites such as short chain fatty acids (SCFA)., Methods: IDA was experimentally induced through an iron deficient diet for a period of 40 days, with twenty weaned male Wistar rats being randomly divided into control or anaemic groups. Blood samples were collected to control haematological parameters, and so were faecal and intestinal content samples to study gut microbial communities and SCFA, using 16S rRNA sequencing and HPLC-UV respectively., Results: An intestinal dysbiosis was observed as a consequence of IDA, especially towards the distal segments of the gastrointestinal tract and the colon. An increase in SCFA was also noticed during IDA, with the major difference appearing in the colon and correlating with changes in the composition of the gut microbiome. Clostridium&#95;sensu&#95;stricto&#95;1 and Clostridium&#95;sensu&#95;stricto&#95;4 showed the greatest correlation with variations in butyric and propionic concentrations in the colon of anaemic animals., Conclusions: Composition of intestinal microbial communities was affected by the generation of IDA. An enrichment in certain SCFA-producing genera and SCFA concentrations was found in the colon of anaemic animals, suggesting a trade-off mechanism against disease., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Difficulty in obtaining adequate abdominal wall closure due to loss of the abdominal domain is a frequent complication of multivisceral, isolated intestinal transplantation and in some cases of liver transplantation. Various methods for primary closure have been proposed, including the use of synthetic and biological meshes, as well as full-thickness abdominal wall and non-vascularized rectus fascia grafts. We describe a novel technique for abdominal wall procurement in which the graft is perfused synchronously with the abdominal organs and can be transplanted as a full-thickness wall or as a non-vascularized rectus fascia graft. We performed six transplants of non-vascularized rectus fascia in three intestinal transplants, one multivisceral transplant, and two liver transplants. The size of the covered abdominal wall defects ranged from 17 cm × 7 cm to 25 cm × 20 cm. Only one patient developed graft infection secondary to enterocutaneous fistula requiring surgical correction and removal of the fascia graft. This patient, as well as two other patients, died due to sepsis. Our procurement technique allows removal of the rectus fascia graft to cover the abdominal wall defect, providing a feasible solution for treatment of abdominal wall defects in recipients after abdominal organ transplantation., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Iron deficiency and iron overload can affect the normal functioning of the innate and adaptive immune responses. Fermented milk products may enhance immune functions, but little is known about the effect of fermented milks on modulation of the immune response during iron deficiency anemia and recovery with normal or high dietary iron intake. Eighty male Wistar rats were randomly assigned to a control group fed a standard diet or to an anemic group fed a diet deficit in iron. Control and anemic groups were fed for 30 days with diets based on a fermented goat's or cow's milk product, with normal iron content or iron overload., Results: In general, during anemia recovery lectin and alternative complement pathway activity and lactoferrin decreased, because it improves iron homeostasis, which is critically important in immune system functions. Fermented goat's milk diet enhanced immune function during iron deficiency recovery, suppressed oxidant-induced eotaxin and fractalkine expression due to the concurrent reduction of free radical production and pro-inflammatory cytokines, and decreased monocyte chemoattractant protein-1 and monocyte migration and adhesion. The increase in interferon-γ can confer immunological colonization of gut microbiota and downregulate inflammation., Conclusion: Fermented goat's milk consumption enhances immune function, modifying complement pathway activity and decreasing pro-inflammatory cytokines as well as lactoferrin concentration, due to the improvement of iron homeostasis, which is critically important in the normal function of the immune system. © 2021 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2021 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

The organisational life cycle assessment (O-LCA) and the social organisational life cycle assessment (SO-LCA) of the University of the Basque Country UPV/EHU were conducted. The data presented in this paper support the calculation of the environmental and social footprint of the University of the Basque Country UPV/EHU for year 2016 [1], and may be used as a reference for future calculations of the environmental and social footprint of higher education institutions and other organisations. This dataset provides detailed information on the UPV/EHU and the boundaries considered; on the compilation and quantification of the life cycle inventory (LCI) -which included a transport survey conducted in summer 2018-; and on the modelling process followed for the calculation of the environmental and social footprints, based on the ecoinvent 3.3 database [2] and PSILCA-based Soca v1 add-on [3, 4], and carried out with the openLCA free software [5]. The dataset also includes the life cycle impact assessment (LCIA) results provided by the CML (baseline, 2015) [6] and ReCiPe (endpoint (H), 2008) [7] LCIA methods and post-processed social impacts provided by the Social Impacts Weighting Method [3], disaggregated by subprocesses and impact locations. Data is provided for the reference year (2016), and some aggregated data is also provided for alternative scenarios that were explored in order to check pathways to reduce social and environmental impacts of the academic activity of the UPV/EHU [1]., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article., (© 2022 The Author(s). Published by Elsevier Inc.)

X-linked hypophosphatemia (XLH), the most common form of hereditary hypophosphatemic rickets, is caused by inactivating mutations of the phosphate-regulating endopeptidase gene (PHEX). XLH is mainly characterized by short stature, bone deformities and rickets, while in hypophosphatemia, normal or low vitamin D levels and low renal phosphate reabsorption are the principal biochemical aspects. The cause of growth impairment in patients with XLH is not completely understood yet, thus making the study of the growth plate (GP) alterations necessary. New treatment strategies targeting FGF23 have shown promising results in normalizing the growth velocity and improving the skeletal effects of XLH patients. However, further studies are necessary to evaluate how this treatment affects the GP as well as its long-term effects and the impact on adult height.

COVID-19 pathophysiology is currently not fully understood, reliable prognostic factors remain elusive, and few specific therapeutic strategies have been proposed. In this scenario, availability of biomarkers is a priority. MS-based Proteomics techniques were used to profile the proteome of 81 plasma samples extracted in four consecutive days from 23 hospitalized COVID-19 associated pneumonia patients. Samples from 10 subjects that reached a critical condition during their hospital stay and 10 matched non-severe controls were drawn before the administration of any COVID-19 specific treatment and used to identify potential biomarkers of COVID-19 prognosis. Additionally, we compared the proteome of five patients before and after glucocorticoids and tocilizumab treatment, to assess the changes induced by the therapy on our selected candidates. Forty-two proteins were differentially expressed between patients' evolution groups at 10% FDR. Twelve proteins showed lower levels in critical patients (fold-changes 1.20-3.58), of which OAS3 and COG5 found their expression increased after COVID-19 specific therapy. Most of the 30 proteins over-expressed in critical patients (fold-changes 1.17-4.43) were linked to inflammation, coagulation, lipids metabolism, complement or immunoglobulins, and a third of them decreased their expression after treatment. We propose a set of candidate proteins for biomarkers of COVID-19 prognosis at the time of hospital admission. The study design employed is distinctive from previous works and aimed to optimize the chances of the candidates to be validated in confirmatory studies and, eventually, to play a useful role in the clinical practice., (© 2022. The Author(s).)

Purpose: In the event that any ocular parameter involved in the calculation of intraocular lens power could not be properly measured in one eye, it is important to know whether clinically relevant differences between both eyes can be expected. The aim of this work is to evaluate the symmetry of interocular biometric parameters., Methods: This was a prospective, cross-sectional study involving 4090 subjects. Patients underwent consecutive swept-source optical biometry performed with an IOLMaster 700 (Carl Zeiss Meditec AG, Jena, Germany). The biometric parameters that were evaluated were: axial length (AL), mean anterior curvature (Rm), anterior chamber depth (ACD), crystalline lens thickness (LT), central corneal thickness (CCT) and white-to-white (WTW). The Chang-Waring chord distance (CWC-D) and the Chang-Waring chord angle (CWC-A) were also evaluated., Results: There is an excellent correlation between both eyes for almost all the biometric parameters under study, with the exception of the CWC. Agreement for AL was better for eyes shorter than 24 mm. The linearity of the OD-vs-OS relationship can be correctly assumed for all parameters (Cusum test: p > 0.05 in all cases)., Conclusion: There are no clinically significant interocular differences for the biometric parameters under study, although for all of them, except the LT, statistically significant differences did arise. In the case of AL, moderate differences can be expected in eyes larger than 24 mm., (© 2021. The Author(s).)

Purpose: This study had three aims: (1) correlate axial length (AL), age and best-corrected visual acuity in high myopic patients scored on the ATN grading system; (2) determine AL cut-off values to distinguish between pathologic myopia (PM) and severe PM; and (3) identify clinical differences between PM and severe PM., Methods: This is a cross-sectional, non-interventional study. All patients underwent complete ophthalmologic examination, ATN grading and multimodal imaging (colour fundus photography, swept-source OCT, fundus autofluorescence, OCT angiography and fluorescein angiography)., Results: Six hundred forty-four eyes from 345 high myopic patients were included. The eyes were graded on the ATN system and classified as PM (≥ A2) or severe PM (≥ A3, ≥ T3 and/or N2). Significant between-group (PM vs. severe PM) differences (p < 0.05) were observed on the individual ATN components (atrophic [A], tractional [T] and neovascular [N]), age, BCVA and AL. AL was also linearly correlated with the A, T and N components (r = 0.53, p < 0.01; r = 0.24, p < 0.01; r = 0.20, p < 0.01; respectively). ROC curve analysis showed the optimal AL cut-off value to distinguish between PM at 28 mm (AUC ROC curve: 0.813, specificity: 75%, sensitivity: 75%) and severe PM at 29.50 mm (AUC ROC curve: 0.760, specificity: 75%, sensitivity: 70%)., Conclusion: AL is the main variable associated with myopic maculopathy. Due to the clinical differences found between PM and severe PM, there is need to create an objective cut-off point to distinguish these two different entities being the optimal cut-off points for AL 28 mm and 29.5 mm, respectively. These objective AL cut-off values should be taken into account for determining a correct follow-up, ophthalmic management and treatment., (© 2021. The Author(s).)

We conducted an international multicentre evaluation to assess the clinical performance characteristics of the new multiplex PCR-based BD MAX Check-Points CPO assay to detect the 5 major carbapenemase families: KPC, VIM/IMP (tested simultaneously), NDM and OXA-48 compared to a reference method consisting of 2 culture methods (to improve recovery of CPO isolates from the rectal swabs), followed by carbapenem susceptibility testing and sequencing of target carbapenemase genes. Tests were performed from rectal swab specimens in ESwab collection and transport devices. Positive percent agreement (PPA) for BD MAX Check-Points CPO for KPC and OXA-48 were 88.2% (95% CI:72.6-96.7) and 96.2% (95% CI:80.4-99.9), respectively. Negative percent agreement was ≥99% for each gene. Insufficient samples (≤10) were positive for VIM/IMP or NDM tests to calculate meaningful PPA values. The BD MAX Check-Points CPO assay represents an accurate tool for rapid recognition of patients with rectal colonization by the most commonly encountered CPOs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To study perforating scleral vessels (PSVs) in patients with high myopia using swept-source optical coherence tomography and to determine their relationship with myopic choroidal neovascularization (mCNV) and its activity., Methods: Retrospective analysis of patients with high myopia (≥-6 D or ≥26 mm of axial length) using multimodal imaging. The presence of PSVs and mCNV was assessed using swept-source optical coherence tomography images (TRITON; Topcon Corporation, Japan)., Results: Five hundred sixty-four eyes from 297 highly myopic patients were studied. One hundred fifty-five eyes (27.5%) showed signs of mCNV while PSVs were found in 500 eyes (88.6%). Perforating scleral vessels were found in 93.5% (145/155) of eyes with mCNV, and they were under or in contact with the mCNV in 80.6% (117/145). The mean number of intravitreal injections received by patients with mCNV was 4.06 ± 4.17 along 66.9 ± 4.1 months of follow-up. The number of injections per year was 1.32 ± 1.56, the mean number of relapses was 1.11 ± 1.83, and the mean number of relapses per year was 0.25 ± 0.41., Conclusion: Perforating scleral vessels are more common among highly myopic patients suffering from neovascular complications. Myopic CNV complexes that are coincident with PSVs on optical coherence tomography show higher rates of activity, needing more injections to control them and being more prone to relapses., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

DNA-RNA hybrids are required for several natural processes in the cell, such as replication and transcription. However, the misregulation of its metabolism is an important source of genetic instability, a hallmark of diseases including cancer. For this reason, genome-wide detection of DNA-RNA hybrids is becoming essential to identify new factors that play a role in its formation or resolution and to understand the global changes in its dynamics because of genetic alterations or chemical treatments. Here, we describe two different immunoprecipitation-based procedures for the genome-wide profiling of DNA-RNA hybrids in the yeast Saccharomyces cerevisiae: DRIP-seq and DRIPc-seq., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Compare subjective (Rx) and objective (ObjRx) refractions outcomes with two autorefractors models and an aberrometer in eyes implanted with a hydrophobic trifocal IOL (FineVision POD F GF, Physiol, Liége, Belgium) and a hydrophilic one (FineVision POD F, Physiol, Liége, Belgium)., Methods: Prospective comparative cohort study, with 100 subjects randomly assigned to either the POD F group (n = 50) or the POD F-GF group (n = 50). Postoperative eye examinations at 1-month visit included seven result sets, one for each assessment method: Rx, AR (automated refraction measured with the autorefractor KR8800), WF-P (Zernike-coefficients-based objective refraction, photopic pupil size), WF-M (Zernike-coefficients-based objective refraction, mesopic pupil size), WF-4 (Zernike-coefficients-based objective refraction, 4 mm pupil), OPD-C (automated refraction measured with the aberrometer OPD in the central pupil/photopic conditions), and OPD-M (automated refraction measured with the aberrometer OPD under mesopic conditions)., Results: Mean differences between ObjRx and Rx reached statistical significance for sphere and spherical equivalent (M) only with OPD-C in the POD F-GF group. All ObjRx methods showed significant differences with Rx in the POD F group, with some values differing by more than 0.50 D (-0.58 D in M for the WF-P). Bland Altman plots showed better agreement for the astigmatic components, and for sphere and spherical equivalents in both IOL groups measured with AR and OPD-M., Conclusions: None of the objective methods of refraction evaluated in this study were as reliable as the subjective refraction, irrespective of the lens material, but POD F-GF ObjRx seems to differ less with Rx than POD F ObjRx values.

Introduction: There is no consensus on the management of the coronavirus disease (COVID-19) in patients with secondary immunosuppression due to either an underlying hematological disease or to the effects of immunochemotherapy (ICT). Some of them may present persistent infection with multiple relapses of COVID-19, requiring several admissions. This study evaluated the clinical characteristics and outcomes after treatment of 5 patients with follicular lymphoma (FL), previously treated with ICT, who developed several episodes of COVID-19., Methods: We analyzed the clinical evolution and response to treatment with antiviral agent, steroids, and convalescent plasma in 5 patients with FL and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persistent infection. Reverse transcriptase polymerase chain reaction tests and peripheral blood immunophenotype were performed for all patients., Results: All patients required hospitalization due to pneumonia with severity criteria and were re-admitted after a median of 22 days (13-42) from the previous discharge. They all showed B-cell depletion by immunophenotyping, and no traces of immunoglobulin antibodies against SARS-CoV-2 were detected in any of the cases. The survival rate was 80%., Conclusion: The combination therapy evidenced clinical benefits, demonstrating its capacity to control infection in immunosuppressed FL patients treated with ICT., (© 2021 S. Karger AG, Basel.)

Projection neurons are the commonest neuronal type in the mammalian forebrain and their individual characterization is a crucial step to understand how neural circuitry operates. These cells have an axon whose arborizations extend over long distances, branching in complex patterns and/or in multiple brain regions. Axon length is a principal estimate of the functional impact of the neuron, as it directly correlates with the number of synapses formed by the axon in its target regions; however, its measurement by direct 3D axonal tracing is a slow and labor-intensive method. On the contrary, axon length estimations have been recently proposed as an effective and accessible alternative, allowing a fast approach to the functional significance of the single neuron. Here, we analyze the accuracy and efficiency of the most used length estimation tools-design-based stereology by virtual planes or spheres, and mathematical correction of the 2D projected-axon length-in contrast with direct measurement, to quantify individual axon length. To this end, we computationally simulated each tool, applied them over a dataset of 951 3D-reconstructed axons (from NeuroMorpho.org), and compared the generated length values with their 3D reconstruction counterparts. The evaluated reliability of each axon length estimation method was then balanced with the required human effort, experience and know-how, and economic affordability. Subsequently, computational results were contrasted with measurements performed on actual brain tissue sections. We show that the plane-based stereological method balances acceptable errors (~5%) with robustness to biases, whereas the projection-based method, despite its accuracy, is prone to inherent biases when implemented in the laboratory. This work, therefore, aims to provide a constructive benchmark to help guide the selection of the most efficient method for measuring specific axonal morphologies according to the particular circumstances of the conducted research., Competing Interests: The authors have declared that no competing interests exist.

Objective: Different adipokines have been reported to play a role in the development, progression, and severity of knee osteoarthritis, but this association may be mediated by obesity. The aim of this study was to evaluate separately the associations of leptin and adiponectin with clinical severity and inflammatory markers in nonobese and obese women with knee osteoarthritis., Design: Cross-sectional study with systematic inclusion of 115 women with symptomatic primary knee osteoarthritis. Age, physical exercise, symptoms duration, and body mass index were collected. Radiographic severity was evaluated according to Kellgren-Lawrence scale. Pain and disability were assessed by WOMAC-total, -pain, -function subscales. Two adipokines (leptin and adiponectin) and 3 inflammatory markers (TNF-α, hsCRP, and IL-6) were measured by ELISA in synovial fluid and serum., Results: Synovial fluid adiponectin was associated with WOMAC pain, function, and total and with synovial fluid IL-6 in nonobese female knee osteoarthritis after controlling by confounders (partial correlation coefficient [PCC] = 0.395, 0.387, 0.427, and 0.649, respectively). Synovial fluid and serum leptin were significantly associated with IL-6 (PCC = 0.354) after controlling by confounders but associations with clinical severity and the rest of inflammatory markers were mitigated after control., Conclusions: Adiponectin in synovial fluid was associated with clinical severity and local inflammatory markers in knee osteoarthritis women, while leptin relation was attenuated when controlled by confounders.

Human milk (HM) is considered the most complete food for infants as its nutritional composition is specifically designed to meet infant nutritional requirements during early life. HM also provides numerous biologically active components, such as polyunsaturated fatty acids, milk fat globules, IgA, gangliosides or polyamines, among others; in addition, HM has a "bifidogenic effect", a prebiotic effect, as a result of the low concentration of proteins and phosphates, as well as the presence of lactoferrin, lactose, nucleotides and oligosaccharides. Recently, has been a growing interest in HM as a potential source of probiotics and commensal bacteria to the infant gut, which might, in turn, influence both the gut colonization and maturation of infant immune system. Our review aims to address practical approaches to the detection of microbial communities in human breast milk samples, delving into their origin, composition and functions. Furthermore, we will summarize the current knowledge of how HM microbiota dysbiosis acts as a short- and long-term predictor of maternal and infant health. Finally, we also provide a critical view of the role of breast milk-related bacteria as a novel probiotic strategy in the prevention and treatment of maternal and offspring diseases.

The Hodgkin lymphoma (HL) genomic landscape is hardly known due to the scarcity of tumour cells in the tissue. Liquid biopsy employing circulating tumour DNA (ctDNA) can emerge as an alternative tool for non-invasive genotyping. By using a custom next generation sequencing (NGS) panel in combination with unique molecule identifiers, we aimed to identify somatic variants in the ctDNA of 60 HL at diagnosis. A total of 277 variants were detected in 36 of the 49 samples (73·5%) with a good quality ctDNA sample. The median number of variants detected per patient was five (range 1-23) with a median variant allele frequency of 4·2% (0·84-28%). Genotyping revealed somatic variants in the following genes: SOCS1 (28%), IGLL5 (26%), TNFAIP3 (23%), GNA13 (23%), STAT6 (21%) and B2M (19%). Moreover, several poor prognosis features (high LDH, low serum albumin, B-symptoms, IPI ≥ 3 or at an advanced stage) were related to significantly higher amounts of ctDNA. Variant detection in ctDNA by NGS is a feasible approach to depict the genetic features of HL patients at diagnosis. Our data favour the implementation of liquid biopsy genotyping for the routine evaluation of HL patients., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Background: The McCluskey index has been used as a tool to predict massive bleeding (>6 red blood cells units) during orthotropic liver transplantation. The objective of this study is to verify its efficacy at our institution., Materials and Methods: Between May 1998 and December 2017, we performed 1216 orthotropic liver transplantations, of which 1016 had sufficient data registered with respect to hemoderivative transfusion. We divided these patients into groups based on the original study of McCluskey. This study was approved by the ethical committee of our Institution and was performed in accordance with the Declaration of Helsinki., Results: The mean Model for End-Stage Liver Disease score in the 4 groups was 7.5 (range, 7-8) for low risk; 13 (range, 3-32) for medium risk, 17 (range, 8-41) for high risk, and 25 (range, 11-36) for very high risk (P < .001). No significant differences were observed regarding body mass index or hospital stay. No differences have been found in the number of suboptimal donors among the groups. With respect to hemoderivative transfusions, we observed the following for red blood cells: 7 (range, 6-8) units for low risk; 5.5 (range, 0-74) for medium risk; 7 (range, 0-73) for high risk, and 12 (range, 5-30) for very high risk (P < .001) and transfusion of plasma: 12 (range, 10-15) units for low risk; 11 (range, 0-89) for medium risk; 14 (range, 0-76) for high risk, and 13 (range, 3-30) for very high risk (P = .001)., Conclusions: The McCluskey index is a good indicator of the risk of hemorrhage and hence the necessity of transfusion., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To evaluate the sources of information used by the Regional Population-based Registries of Rare Diseases (RRD) for Wilson's Disease identification in Spain; to calculate its prevalence and mortality; and to describe the sociodemographic characteristics of those affected., Method: Cross-sectional epidemiological study, period 2010-2015. Possible cases were identified by codes 275.1 (ICD-9-CM), E83.0 (ICD-10) and 905 (ORPHAcode) in: 15 participating RRD and the Rare Disease Patients Registry of the Carlos III Health Institute. The diagnoses were confirmed through a clinical documentation review. The positive predictive value (PPV) of the sources of information used by RRD and their combinations were obtained. The prevalence, mortality and the distribution of sociodemographic characteristics were calculated., Results: The Hospital Discharge Database (HDD) was the most used source by the RRD (PPV=39.4%), followed by the Orphan Drugs Registry (ODR) (PPV=81.9%). The Clinical History of Primary Care (PC) obtains PPV=55.9%. The combinations with highest PPV were the ODR with HDD (PPV=95.8%) and the ODR with PC (PPV=92.9%). 514 cases were confirmed, 57.2% men, with a median age of diagnosis of 21.3 years. The prevalence was 1.64/100,000 inhabitants in 2015 and mortality rate was 3.0%, being both higher in men., Conclusions: Incorporation of ODR and PC into the RRD is recommended, as its combination and ODR with HDD could be used as an automatic validation criterion for Wilson's disease. The prevalence obtained was similar to that of countries close to Spain., (Copyright © 2020 SESPAS. Publicado por Elsevier España, S.L.U. All rights reserved.)

Transcription is an essential process of DNA metabolism, yet it makes DNA more susceptible to DNA damage. THSC/TREX-2 is a conserved eukaryotic protein complex with a key role in mRNP biogenesis and maturation that prevents genome instability. One source of such instability is linked to transcription, as shown in yeast and human cells, but the underlying mechanism and whether this link is universal is still unclear. To obtain further insight into the putative role of the THSC/TREX-2 complex in genome integrity, we have used Caenorhabditis elegans mutants of the thp-1 and dss-1 components of THSC/TREX-2. These mutants show similar defective meiosis, DNA damage accumulation and activation of the DNA damage checkpoint. However, they differ from each other regarding replication defects, as determined by measuring dUTP incorporation in the germline. Interestingly, this specific thp-1 mutant phenotype can be partially rescued by overexpression of RNase H. Furthermore, both mutants show a mild increase in phosphorylation of histone H3 at Ser10 (H3S10P), a mark previously shown to be linked to DNA-RNA hybrid-mediated genome instability. These data support the view that both THSC/TREX-2 factors prevent transcription-associated DNA damage derived from DNA-RNA hybrid accumulation by separate means., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Alport syndrome is a genetic and hereditary disease, caused by mutations in the type IV collagen genes COL4A3 , COL4A4 and COL4A5 , that affects the glomerular basement membrane of the kidney. It is a rare disease with an underestimated prevalence. Genetic analysis of population cohorts has revealed that it is the second most common inherited kidney disease after polycystic kidney disease. Renal involvement is the main manifestation, although it may have associated extrarenal manifestations such as hearing loss or ocular problems. The degree of expression of the disease changes according to the gene affected and other factors, known or yet to be known. The pathophysiology is not yet fully understood, although some receptors, pathways or molecules are known to be linked to the disease. There is also no specific treatment for Alport syndrome; the most commonly used are renin-angiotensin-aldosterone system inhibitors. In recent years, diagnosis has come a long way, thanks to advances in DNA sequencing technologies such as next-generation sequencing (NGS). Further research at the genetic and molecular levels in the future will complete the partial vision of the pathophysiological mechanism that we have, and will allow us to better understand what is happening and how to solve it.

Purpose: To study clinical features in patients with ridge-shaped macula (RSM) compared with those with dome-shaped macula (DSM) having been previously classified by the number of swept-source optical coherence tomography (SS-OCT) radial scans affected., Methods: Retrospective observational study including 49 highly myopic eyes from 31 patients who underwent SS-OCT. DSM eyes were defined as those that showed a complete round inward convexity in all their axes, presenting an inward convexity ≥50 µm in the 12-line radial OCT scans. Eyes that did not meet this criterion and had at least one flat radial scan were grouped into the RSM group, defined as a macular inward convexity in some meridians across the fovea, whereas the opposite perpendicularly oriented meridians were flat. Age, spherical equivalent, axial length (AL), and best-corrected visual acuity (BCVA) were collected. Height of the bulge, scleral and choroidal thicknesses, Bruch´s membrane defects, and presence of perforating scleral vessels were recorded., Results: Thirty-seven (75.5%) eyes were classified into the RSM group and 12 (24.5%) into the DSM group. Twenty-six (53.0%) eyes showed macular elevation only in the horizontal direction. Mean AL showed statistically significant differences (28.8 ± 2.7 vs. 30.5 ± 1.5 mm in the RMS vs. DSM group, respectively) and the presence of Bruch´s membrane defects was more frequently seen in DSM ( p < 0.001). Mean age, spherical equivalent, BCVA, height of the inward convexity, retinal foveal thickness, foveal scleral thickness, subfoveal choroidal thickness, and the presence of perforating scleral vessels did not show significant differences between groups., Conclusion: This study shows the reliability of using the 12 equal radial OCT scans as an objective method to define and differentiate DSM versus RSM. Patients with RSM showed differences in AL compared with those with DSM, being longer in DSM, and regarding the presence of Bruch´s membrane defects, being more common in DSM. This may contribute to identifying those patients that, in daily clinical practice, have a higher risk of developing complications due to their myopia.

Soft rot disease of edible mushrooms leads to rapid degeneration of fungal tissue and thus severely affects farming productivity worldwide. The bacterial mushroom pathogen Burkholderia gladioli pv. agaricicola has been identified as the cause. Yet, little is known about the molecular basis of the infection, the spatial distribution and the biological role of antifungal agents and toxins involved in this infectious disease. We combine genome mining, metabolic profiling, MALDI-Imaging and UV Raman spectroscopy, to detect, identify and visualize a complex of chemical mediators and toxins produced by the pathogen during the infection process, including toxoflavin, caryoynencin, and sinapigladioside. Furthermore, targeted gene knockouts and in vitro assays link antifungal agents to prevalent symptoms of soft rot, mushroom browning, and impaired mycelium growth. Comparisons of related pathogenic, mutualistic and environmental Burkholderia spp. indicate that the arsenal of antifungal agents may have paved the way for ancestral bacteria to colonize niches where frequent, antagonistic interactions with fungi occur. Our findings not only demonstrate the power of label-free, in vivo detection of polyyne virulence factors by Raman imaging, but may also inspire new approaches to disease control., (© 2021 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

The spike protein is the main protein component of the SARS-CoV-2 virion surface. The spike receptor-binding motif mediates recognition of the human angiotensin-converting enzyme 2 receptor, a critical step in infection, and is the preferential target for spike-neutralizing antibodies. Posttranslational modifications of the spike receptor-binding motif have been shown to modulate viral infectivity and host immune response, but these modifications are still being explored. Here we studied asparagine deamidation of the spike protein, a spontaneous event that leads to the appearance of aspartic and isoaspartic residues, which affect both the protein backbone and its charge. We used computational prediction and biochemical experiments to identify five deamidation hotspots in the SARS-CoV-2 spike protein. Asparagine residues 481 and 501 in the receptor-binding motif deamidate with a half-life of 16.5 and 123 days at 37 °C, respectively. Deamidation is significantly slowed at 4 °C, indicating a strong dependence of spike protein molecular aging on environmental conditions. Deamidation of the spike receptor-binding motif decreases the equilibrium constant for binding to the human angiotensin-converting enzyme 2 receptor more than 3.5-fold, yet its high conservation pattern suggests some positive effect on viral fitness. We propose a model for deamidation of the full SARS-CoV-2 virion illustrating how deamidation of the spike receptor-binding motif could lead to the accumulation on the virion surface of a nonnegligible chemically diverse spike population in a timescale of days. Our findings provide a potential mechanism for molecular aging of the spike protein with significant consequences for understanding virus infectivity and vaccine development., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate visual function, ocular surface integrity and dry eye symptoms with an extended depth-of-focus (EDOF) design and a conventional multifocal (MF) contact lens (CL) after 15 days of wear., Methods: A crossover single mask randomised clinical trial was conducted including 30 presbyopes who used an EDOF and a conventional MF CL (Biofinity MF) for 15 days each. Defocus curves, depth-of-focus range, contrast sensitivity (CS) under photopic and mesopic conditions (with and without glare) and subjective perception of halos and glare were evaluated. The ocular surface was evaluated through non-invasive Keratograph tear breakup time (NIKBUT), averaged tear breakup time (NIKBUT-avg), tear meniscus height (TMH), bulbar and limbal redness, and conjunctival and corneal staining. Dry eye symptoms were assessed with the OSDI questionnaire., Results: No statistically significant differences were found for defocus curves or depth-of-focus between the two CLs (both p > 0.05). Subjective perception of halos and glare was not significantly different between CLs. Statistically significant differences were observed for CS under mesopic conditions for low spatial frequencies (p = 0.008). None of the CL produced significant changes in NIKBUT, NIKBUT-avg, TMH or redness. No change in conjunctival staining was observed in 76.7 % and 73.3 % of participants for EDOF and Biofinity MF, respectively. No change in corneal staining was observed in 86.7 % and 83.3 % of participants for EDOF and Biofinity MF, respectively. No changes were observed in the symptomatology measured with OSDI questionnaire (p > 0.05)., Conclusions: Both CL for presbyopia offer good visual quality, preserve the ocular surface integrity and provide the patient with similar symptomatology levels after 15 days of lens wear., (Copyright © 2020 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Background: Because of their specific and biologically relevant cargo, urine extracellular vesicles (EVs) constitute a valuable source of potential non-invasive biomarkers that could support the clinical decision-making to improve the management of prostate cancer (PCa) patients. Different EV isolation methods differ in terms of complexity and yield, conditioning, as consequence, the analytical result., Methods: The aim of this study was to compare three different isolation methods for urine EVs: ultracentrifugation (UC), size exclusion chromatography (SEC), and a commercial kit (Exolute® Urine Kit). Urine samples were collected from 6 PCa patients and 4 healthy donors. After filtered through 0.22 µm filters, urine was divided in 3 equal volumes to perform EVs isolation with each of the three approaches. Isolated EVs were characterized by spectrophotometric protein quantification, nanoparticle tracking analysis, transmission electron microscopy, AlphaScreen Technology, and whole miRNA Transcriptome., Results: Our results showed that UC and SEC provided better results in terms of EVs yield and purity than Exolute®, non-significant differences were observed in terms of EV-size. Interestingly, luminescent AlphaScreen assay demonstrated a significant enrichment of CD9 and CD63 positive microvesicles in SEC and UC methods compared with Exolute®. This heterogeneity was also demonstrated in terms of miRNA content indicating that the best correlation was observed between UC and SEC., Conclusions: Our study highlights the importance of standardizing the urine EV isolation methods to guaranty the analytical reproducibility necessary for their implementation in a clinical setting., (© 2021. The Author(s).)